Induction and circumvention of nitrate tolerance applying different dosage intervals

Silber, Sigmund; Vogler, Astrid C.; Krause, Karl‐Heinz; Vogel, Margot; Theisen, K.

doi:10.1016/0002-9343(87)90643-7

Cited by 50 publications

(18 citation statements)

References 37 publications

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“…Contradictory results have been reported on the development of tolerance to long term treatment with nitrates [4,10,11]. No signs of tolerance appeared in our study, although myocardial ischemia, indicated by ST-D, was higher in the 6th week of medica tion (12 h after administration of IS-5-MN, respectively 24 h after AT) than in the 2nd and the 4th weeks with monotherapy or combination therapy.…”

Section: Commentsupporting

confidence: 56%

Isosorbide-5-Mononitrate and Atenolol in the Treatment of Stable Exertional Angina

Waysbort

Meshulam²,

Brunner³

1991

Cardiology

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Fourteen men and six women, 48–68 years old, with stable angina and effort-induced ST-segment depression (ST-D) were treated with isosorbide-5-mononitrate (IS-5-MN) 2 × 40 mg/day and/or atenolol (AT) 100 mg/day in a double-blind randomized sequence during two 6-week periods. The patients performed ergometer tests. AT caused more decrease of heart rate at rest and at comparable work-load than IS-5-MN. Blood pressure at rest was in the normal range. Decrease of blood pressure at rest and at effort was similar with both agents. Combined administration of the two drugs was not more effective than monotherapy with AT or IS-5-MN in lowering heart rate and blood pressure. The average ST-D at comparable effort was for placebo 2.3 mm, for IS-5-MN after 2, 4, and 6 weeks, 3, 6, and 12 h, respectively, after medication, 1.4, 1.0, and 1.3 mm, and for AT 1.2, 1.4, and 1.4 mm, respectively. Administration of the drugs together caused additional highly significant reduction of ST-D (0.3–0.9 mm). The results indicate that IS-5-MN and AT have a similar beneficial effect on effort-induced myocardial ischemia, which is enhanced by their combined administration. The drugs alone and in combination are effective for as long as 12 h after administration of IS-5-MN, and 24 h after administration of AT. Moderate signs of tolerance to IS-5-MN were found after 6 weeks of therapy.

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Section: Commentsupporting

confidence: 56%

Isosorbide-5-Mononitrate and Atenolol in the Treatment of Stable Exertional Angina

Waysbort

Meshulam²,

Brunner³

1991

Cardiology

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“…In particular, after continuous therapy with transdermal glyceryl trinitrate was begun in the USAand found to be ineffective (22), the usefulness of a "patch-off period was proposed for transdermal patch treatment (4,5,8,21). Moreover, beneficial effects of intermittent administration were also reported for oral ISDN (7,23) and ISMN (7,10,15).…”

Section: Discussionmentioning

confidence: 99%

Intermittent Nitrate Therapy for Prior Myocardial Infarction Does Not Induce Rebound Angina nor Reduce Cardiac Events.

et al. 2000

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Objective Long-term nitrate therapy for ischemic heart disease may cause drug tolerance which diminishes its beneficial effects ; consequently, intermittent administration of nitrates is recommended. With this regimen, however, the potential occurrence of rebound angina during the nitratefree intervals is a source of concern. Subjects and MethodsWecarried out a retrospective study of 606 patients to determine whether rebound angina occurred whenconventional continuousnitrate administration was replaced by intermittent administration as part of a long-term therapy protocol for prior myocardial infarction. Thesubjects were receiving treatment for myocardial infarction and included 293 patients treated with nitrates (Nitrate group) and 313 patients who were not (Nonitrate group). The former included 186 patients who received intermittent nitrate administration (Intermittent group) and 107 patients who received continuous administration (Continuous group). The mean period of observation was 4.3+1.6 months.

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“…Such a dose regimen has also been claimed to be of continuous efficacy [22] or to have shown only a minimally reduced antianginal efficacy after 1 week of therapy [23]. In addition, the twice-daily administration of a sustained-release tablet of 80 mg isosorbide dinitrate caused tolerance when the dosing interval was 12 h (administration at 08.00 h and 20.00 h) but not when the daily dosing intervals were 6 and 18 h (administration at 08.00 h and 14.00 h [24]. Using the latter dosing intervals, minimum plasma concentrations of IS-5-MN are expected to be about 100 ng/ml but they will be higher than 300 ng/ml with the 12-h dosing interval [20].…”

Section: Discussionmentioning

confidence: 99%

Relationship between pharmacokinetics and hemodynamic tolerance to isosorbide-5-mononitrate

Wagner

Siefert

Trenk

et al. 1990

Eur J Clin Pharmacol

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Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen II was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III 60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

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Induction and circumvention of nitrate tolerance applying different dosage intervals

Cited by 50 publications

References 37 publications

Isosorbide-5-Mononitrate and Atenolol in the Treatment of Stable Exertional Angina

Isosorbide-5-Mononitrate and Atenolol in the Treatment of Stable Exertional Angina

Intermittent Nitrate Therapy for Prior Myocardial Infarction Does Not Induce Rebound Angina nor Reduce Cardiac Events.

Relationship between pharmacokinetics and hemodynamic tolerance to isosorbide-5-mononitrate

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